1. Field of the Invention
The present invention is directed to a new process for producing a key intermediate used in the synthesis of thienamycin and other carbapenem antibiotics.
2. Description of the Prior Art
The antibiotic thienamycin of the formula ##STR2## was originally obtained from fermentation of Streptomyces cattleya as described in U.S. Pat. No. 3,950,357. Thienamycin is an exceptionally potent broad-spectrum antibiotic which possesses notable activity against various Pseudomonas species, organisms which have been notoriously resistant to .beta.-lactam antibiotics.
Because of the exceptional biological activity of thienamycin, a large number of derivatives have been prepared. While attempts have been made to synthesize derivatives with various substituents other than hydroxyethyl at the 6-position of the carbapenem ring system, the hydroxyethyl group is still considered the most advantageous 6-substituent for optimum activity.
Other derivatives have been made where the carbapenem nucleus is mono- or disubstituted at the 1-position, preferably with methyl (see, for example, European Patent Application No. 54,917).
Since fermentation procedures to prepare thienamycin and derivatives thereof have been unsatisfactory, several total synthesis procedures have been reported in the literature (see, for example, U.S. Pat. Nos. 4,287,123, 4,269,772, 4,282,148, 4,273,709, 4,290,947, and European Patent Application Nos. 7973 and 54,917). While the various synthetic procedures utilize different starting materials, they go through a common diazo intermediate having the formula ##STR3## where R.sup.5 and R.sup.6 each independently represent hydrogen or methyl and R.sub.1 represents a conventional carboxyl-protecting group. One of the most preferred carboxyl-protecting groups for intermediate I is the p-nitrobenzyl group which can be readily removed by catalytic hydrogenation after formation of the ultimate carbapenem product. Another most preferred protecting group is the allyl ester which can be readily removed with a catalyst comprising a mixture of a palladium compound and triphenylphosphine in an aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride.
Recently attempts have been made to synthesize intermediate I (and subsequently thienamycin and other carbapenem derivatives) from readily available 6-APA. Karady et al., for example, in J. Am. Chem. Soc. 103(22): 6765-6767 (1981) disclose one such process which produces the diazo intermediate of the formula ##STR4## where P is t-butyldimethylsilyl by displacement of the O-protected azetidinone of the formula ##STR5## with an enol silyl ether of benzyl 2-diazoacetoacetate having the formula ##STR6##
Tetrahedron Lett. 23(22): 2293-2296 (1982) discloses the preparation of the diazo intermediate of the formula ##STR7## from 4-acetoxy-3-(1-hydroxyethyl)-2-azetidinone by Lewis acid catalyzed alkylation with the corresponding silyl enol ether of the formula ##STR8##
Yoshida et al. in Chem. Pharm. Bull. 29(10): 2899-2909 (1981) report another synthetic procedure for converting 6-APA to the O-protected azetidinone of the formula ##STR9## which can be converted to a diazo intermediate of Formula I by the process disclosed in the above-mentioned Tetrahedron Lett. reference.
Since the diazo intermediates of Formula I are preferred carbapenem intermediates, it would be desirable to have a process for converting readily available azetidinone compounds of the general formula ##STR10## where L is a conventional leaving group such as halo or acetoxy and P is a conventional hydroxyl-protecting group such as triorganosilyl to the corresponding ester intermediates of Formula I.
Since the Lewis acid catalyzed alkylation of ketones as their silyl enol ethers has been described in the literature (see, for example, Tetrahedron Lett. 23(22): 2293-2296, 1982 and also Tetrahedron Lett. 23(4): 379-382, 1982), it might be expected that the desired ester intermediate I or a hydroxy-protected derivative thereof could be prepared by Lewis acid catalyzed alkylation of an appropriate azetidinone compound II with an enol silyl ether of the diazoacetoacetate ester having the formula ##STR11## wherein R.sup.5 and R.sup.6 are each independently hydrogen or methyl, R.sub.1 is a conventional carboxyl-protecting group and R.sup.1, R.sup.2, and R.sup.3 are each independently C.sub.1 -C.sub.4 alkyl or, alternatively ##STR12## Unfortunately, however, the present inventors have found that the known method of preparing compounds of Formula III does not work when a p-nitrobenzyl protecting group is desired or when the tert-butyldimethylsilyl hydroxyl protecting group is employed. Thus, the prior art method for preparing enol silyl ethers of diazoacetoacetates employs silylation of a diazoacetoacetate ester of the formula ##STR13## wherein R.sub.1 is a carboxyl-protecting group to the enol silyl ether ester ##STR14## by use of a trimethylsilyl halide silylating agent in the presence of a strong base, e.g. trimethylchlorosilane with a lithium base such as lithium hexamethyldisilazide. When this prior art method is employed with the p-nitrobenzyl ester ##STR15## the strong base needed to form the enolate is incompatible with the p-nitrobenzyl ester because of the highly reactive methylene group. Use of weaker organic bases such as trialkylamines with the triorganosilyl halide silylating agent, however, does not produce the desired enol silyl ester. Additionally, the prior art procedure which generally allows preparation of trimethylsilylenolethers of the type ##STR16## where R.sub.1 is a conventional ester protecting group other than a highly reactive ester such as p-nitrobenzyl, was not successful for preparation of the corresponding tert-butyldimethylsilylenolethers which, as pointed out below, are particularly preferred carbapenem intermediates.
It was the object of the present invention to provide a novel and general silylation procedure which would be applicable for producing silylenolethers of the formula ##STR17## where R.sup.5 and R.sup.6 are each independently hydrogen or methyl, R.sub.1 is a conventional carboxyl-protecting group and R.sub.1, R.sup.2, and R.sup.3 are each independently C.sub.1 -C.sub.4 alkyl or, alternatively, ##STR18## from the intermediate ##STR19## wherein R.sup.5, R.sup.6, and R.sub.1 are as defined above.
Successful preparation of intermediate III would then allow preparation of the key carbapenem intermediate ##STR20## or a hydroxyl-protected derivative thereof by reaction of intermediate IIIA with a suitable O-protected azetidinone of the formula ##STR21## wherein P and L are as defined above followed by removal, if desired, of the hydroxyl-protecting group.